Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

A phosphatase cascade by which rewarding stimuli control nucleosomal response


Dopamine orchestrates motor behaviour and reward-driven learning. Perturbations of dopamine signalling have been implicated in several neurological and psychiatric disorders, and in drug addiction. The actions of dopamine are mediated in part by the regulation of gene expression in the striatum, through mechanisms that are not fully understood. Here we show that drugs of abuse, as well as food reinforcement learning, promote the nuclear accumulation of 32-kDa dopamine-regulated and cyclic-AMP-regulated phosphoprotein (DARPP-32). This accumulation is mediated through a signalling cascade involving dopamine D1 receptors, cAMP-dependent activation of protein phosphatase-2A, dephosphorylation of DARPP-32 at Ser 97 and inhibition of its nuclear export. The nuclear accumulation of DARPP-32, a potent inhibitor of protein phosphatase-1, increases the phosphorylation of histone H3, an important component of nucleosomal response. Mutation of Ser 97 profoundly alters behavioural effects of drugs of abuse and decreases motivation for food, underlining the functional importance of this signalling cascade.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Drugs of abuse and food self-administration induce nuclear accumulation of DARPP-32 in striatal neurons.
Figure 2: DARPP-32 undergoes continuous cyto-nuclear shuttling.
Figure 3: Phosphorylation at Ser 97 controls intracellular localization of DARPP-32.
Figure 4: Mutation of Ser 97 alters localization of DARPP-32, behavioural responses to drugs of abuse and motivation for food reward.
Figure 5: Role of nuclear DARPP-32 in the phosphorylation of histone H3 in striatal neurons.


  1. 1

    Schultz, W. & Dickinson, A. Neuronal coding of prediction errors. Annu. Rev. Neurosci. 23, 473–500 (2000)

    CAS  Article  Google Scholar 

  2. 2

    Berke, J. D. & Hyman, S. E. Addiction, dopamine, and the molecular mechanisms of memory. Neuron 25, 515–532 (2000)

    CAS  Article  Google Scholar 

  3. 3

    Di Chiara, G. Drug addiction as dopamine-dependent associative learning disorder. Eur. J. Pharmacol. 375, 13–30 (1999)

    CAS  Article  Google Scholar 

  4. 4

    Everitt, B. J. & Robbins, T. W. Neural systems of reinforcement for drug addiction: from actions to habits to compulsion. Nature Neurosci. 8, 1481–1489 (2005)

    CAS  Article  Google Scholar 

  5. 5

    Nicola, S. M., Surmeier, J. & Malenka, R. C. Dopaminergic modulation of neuronal excitability in the striatum and nucleus accumbens. Annu. Rev. Neurosci. 23, 185–215 (2000)

    CAS  Article  Google Scholar 

  6. 6

    Reynolds, J. N. & Wickens, J. R. Dopamine-dependent plasticity of corticostriatal synapses. Neural Netw. 15, 507–521 (2002)

    Article  Google Scholar 

  7. 7

    Hyman, S. E., Malenka, R. C. & Nestler, E. J. Neural mechanisms of addiction: the role of reward-related learning and memory. Annu. Rev. Neurosci. 29, 565–598 (2006)

    CAS  Article  Google Scholar 

  8. 8

    Walaas, S. I., Aswad, D. W. & Greengard, P. A dopamine- and cyclic AMP-regulated phosphoprotein enriched in dopamine-innervated brain regions. Nature 301, 69–71 (1983)

    ADS  CAS  Article  Google Scholar 

  9. 9

    Svenningsson, P. et al. DARPP-32: an integrator of neurotransmission. Annu. Rev. Pharmacol. Toxicol. 44, 269–296 (2004)

    CAS  Article  Google Scholar 

  10. 10

    Ouimet, C. C. et al. DARPP-32, a dopamine- and adenosine 3′:5′-monophosphate-regulated phosphoprotein enriched in dopamine-innervated brain regions. III. Immunocytochemical localization. J. Neurosci. 4, 111–124 (1984)

    CAS  Article  Google Scholar 

  11. 11

    Hemmings, H. C., Greengard, P., Tung, H. Y. L. & Cohen, P. DARPP-32, a dopamine-regulated neuronal phosphoprotein, is a potent inhibitor of protein phosphatase-1. Nature 310, 503–505 (1984)

    ADS  CAS  Article  Google Scholar 

  12. 12

    Fienberg, A. A. et al. DARPP-32: Regulator of the efficacy of dopaminergic neurotransmission. Science 281, 838–839 (1998)

    ADS  CAS  Article  Google Scholar 

  13. 13

    Valjent, E. et al. Regulation of a protein phosphatase cascade allows convergent dopamine and glutamate signals to activate ERK in the striatum. Proc. Natl Acad. Sci. USA 102, 491–496 (2005)

    ADS  CAS  Article  Google Scholar 

  14. 14

    Brami-Cherrier, K. et al. Parsing molecular and behavioral effects of cocaine in mitogen- and stress-activated protein kinase-1-deficient mice. J. Neurosci. 25, 11444–11454 (2005)

    CAS  Article  Google Scholar 

  15. 15

    Ouimet, C. C. & Greengard, P. Distribution of DARPP-32 in the basal ganglia: An electron microscopic study. J. Neurocytol. 19, 39–52 (1990)

    CAS  Article  Google Scholar 

  16. 16

    Pontieri, F. E., Tanda, G. & Di Chiara, G. Intravenous cocaine, morphine, and amphetamine preferentially increase extracellular dopamine in the ‘shell’ as compared with the ‘core’ of the rat nucleus accumbens. Proc. Natl Acad. Sci. USA 92, 12304–12308 (1995)

    ADS  CAS  Article  Google Scholar 

  17. 17

    Gong, S. et al. A gene expression atlas of the central nervous system based on bacterial artificial chromosomes. Nature 425, 917–925 (2003)

    ADS  CAS  Article  Google Scholar 

  18. 18

    Nishi, K. et al. Leptomycin B targets a regulatory cascade of crm1, a fission yeast nuclear protein, involved in control of higher order chromosome structure and gene expression. J. Biol. Chem. 269, 6320–6324 (1994)

    CAS  Google Scholar 

  19. 19

    Henderson, B. R. & Eleftheriou, A. A comparison of the activity, sequence specificity, and CRM1-dependence of different nuclear export signals. Exp. Cell Res. 256, 213–224 (2000)

    CAS  Article  Google Scholar 

  20. 20

    Stedman, D. R. et al. Cytoplasmic localization of calcium/calmodulin-dependent protein kinase I-α depends on a nuclear export signal in its regulatory domain. FEBS Lett. 566, 275–280 (2004)

    CAS  Article  Google Scholar 

  21. 21

    Rastogi, S., Joshi, B., Fusaro, G. & Chellappan, S. Camptothecin induces nuclear export of prohibitin preferentially in transformed cells through a CRM-1-dependent mechanism. J. Biol. Chem. 281, 2951–2959 (2006)

    CAS  Article  Google Scholar 

  22. 22

    Girault, J. A. et al. Phosphorylation of DARPP-32, a dopamine- and cAMP-regulated phosphoprotein, by casein kinase II. J. Biol. Chem. 264, 21748–21759 (1989)

    CAS  Google Scholar 

  23. 23

    Sarno, S. et al. Selectivity of 4,5,6,7-tetrabromobenzotriazole, an ATP site-directed inhibitor of protein kinase CK2 (‘casein kinase-2’). FEBS Lett. 496, 44–48 (2001)

    CAS  Article  Google Scholar 

  24. 24

    Nishi, A. et al. Amplification of dopaminergic signaling by a positive feedback loop. Proc. Natl Acad. Sci. USA 97, 12840–12845 (2000)

    ADS  CAS  Article  Google Scholar 

  25. 25

    Nishi, A., Snyder, G. L., Nairn, A. C. & Greengard, P. Role of calcineurin and protein phosphatase-2A in the regulation of DARPP-32 dephosphorylation in neostriatal neurons. J. Neurochem. 72, 2015–2021 (1999)

    CAS  Article  Google Scholar 

  26. 26

    Usui, H. et al. Activation of protein phosphatase 2A by cAMP-dependent protein kinase-catalyzed phosphorylation of the 74-kDa B″ (δ) regulatory subunit in vitro and identification of the phosphorylation sites. FEBS Lett. 430, 312–316 (1998)

    CAS  Article  Google Scholar 

  27. 27

    Ahn, J. H. et al. Protein kinase A activates protein phosphatase 2A by phosphorylation of the B56δ subunit. Proc. Natl Acad. Sci. USA 104, 2979–2984 (2007)

    ADS  CAS  Article  Google Scholar 

  28. 28

    Nowak, S. J. & Corces, V. G. Phosphorylation of histone H3: a balancing act between chromosome condensation and transcriptional activation. Trends Genet. 20, 214–220 (2004)

    CAS  Article  Google Scholar 

  29. 29

    Salvador, L. M. et al. Follicle-stimulating hormone stimulates protein kinase A-mediated histone H3 phosphorylation and acetylation leading to select gene activation in ovarian granulosa cells. J. Biol. Chem. 276, 40146–40155 (2001)

    CAS  Article  Google Scholar 

  30. 30

    Murnion, M. E. et al. Chromatin-associated protein phosphatase 1 regulates aurora-B and histone H3 phosphorylation. J. Biol. Chem. 276, 26656–26665 (2001)

    CAS  Article  Google Scholar 

  31. 31

    Hsu, J. Y. et al. Mitotic phosphorylation of histone H3 is governed by Ipl1/aurora kinase and Glc7/PP1 phosphatase in budding yeast and nematodes. Cell 102, 279–291 (2000)

    CAS  Article  Google Scholar 

  32. 32

    Bode, A. M. & Dong, Z. G. Inducible covalent postranslational modification of histone H3. Sci. STKE 281, 1–12 (2005)

    Google Scholar 

  33. 33

    Levenson, J. M. & Sweatt, J. D. Epigenetic mechanisms: a common theme in vertebrate and invertebrate memory formation. Cell. Mol. Life Sci. 63, 1009–1016 (2006)

    CAS  Article  Google Scholar 

  34. 34

    Kumar, A. et al. Chromatin remodeling is a key mechanism underlying cocaine-induced plasticity in striatum. Neuron 48, 303–314 (2005)

    CAS  Article  Google Scholar 

  35. 35

    Poon, I. K. & Jans, D. A. Regulation of nuclear transport: central role in development and transformation? Traffic 6, 173–186 (2005)

    CAS  Article  Google Scholar 

  36. 36

    Panasyuk, G. et al. Nuclear export of S6K1 II is regulated by protein kinase CK2 phosphorylation at Ser-17. J. Biol. Chem. 281, 31188–31201 (2006)

    CAS  Article  Google Scholar 

  37. 37

    Alt, J. R., Cleveland, J. L., Hannink, M. & Diehl, J. A. Phosphorylation-dependent regulation of cyclin D1 nuclear export and cyclin D1-dependent cellular transformation. Genes Dev. 14, 3102–3114 (2000)

    CAS  Article  Google Scholar 

  38. 38

    Beaulieu, J. M. et al. An Akt/β-arrestin 2/PP2A signaling complex mediates dopaminergic neurotransmission and behavior. Cell 122, 261–273 (2005)

    CAS  Article  Google Scholar 

  39. 39

    Nestler, E. J. Molecular basis of long-term plasticity underlying addiction. Nature Rev. Neurosci. 2, 119–128 (2001)

    ADS  CAS  Article  Google Scholar 

  40. 40

    Svenningsson, P. et al. Diverse psychotomimetics act through a common signaling pathway. Science 302, 1412–1415 (2003)

    ADS  CAS  Article  Google Scholar 

  41. 41

    Zhang, Y. et al. Cocaine self-administration in mice is inversely related to phosphorylation at Thr34 (protein kinase A site) and Ser130 (kinase CK1 site) of DARPP-32. J. Neurosci. 26, 2645–2651 (2006)

    CAS  Article  Google Scholar 

  42. 42

    Drago, J. et al. Altered striatal function in a mutant mouse lacking D1A dopamine receptors. Proc. Natl Acad. Sci. USA 91, 12564–12568 (1994)

    ADS  CAS  Article  Google Scholar 

  43. 43

    Vanderschuren, L. J. et al. A single exposure to amphetamine is sufficient to induce long-term behavioral, neuroendocrine, and neurochemical sensitization in rats. J. Neurosci. 19, 9579–9586 (1999)

    CAS  Article  Google Scholar 

  44. 44

    Valjent, E. et al. Involvement of the extracellular signal-regulated kinase cascade for cocaine-rewarding properties. J. Neurosci. 20, 8701–8709 (2000)

    CAS  Article  Google Scholar 

Download references


We thank M. Lambert for her help with time-lapse video; P. Ingrassia and P. Bernard for their help with mutant mice; and M. R. Picciotto, S. Cottecchia, J. P. Hornung, R. Luedtke, M. Takeda and Intracellular Therapies Inc. for reagents. This work was supported by Inserm, and by grants from Agence Nationale de la Recherche (05-NEUR-020-01), Fondation Bettencourt-Schueller (Coup d’élan) and Association pour la Recherche contre le Cancer (ARC-3118 and -7905) to J.A.G., from Fondation pour la Recherche Médicale (FRM) to D.H., a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science to A.N., and grants from the National Institute on Drug Abuse (DA10044), the National Institute of Mental Health (MH74866), the US Department of Defense (W81XWH-05-1-0146), the Picower Foundation, the Michael Stern Parkinson’s Research Foundation and the US Army Medical Research Acquisition Activity (DAMD17-02-1-0705 and W81XWH-05-1-0146) to P.G. and A.C.N. A.S. was supported by Mission Interministérielle de Lutte contre la Drogue et la Toxicomanie and FRM, and J.B.G. by FRM.

Author Contributions A.S. and Mi.M. performed experiments in vivo and in transfected cultures, immunofluorescence and molecular biology. E.V. conducted in vivo, behavioural and immunohistofluorescence experiments. A.S., E.V. and Mi.M. prepared the figures. A.N. performed the slice experiments, J.H.A. the phosphatase experiments, and Ma.M. the incentive learning experiments. J.B.G. and A.G.C. contributed to in vivo and immunohistofluorescence experiments, and K.B.C. and H.E. to cell culture experiments. O.F. provided advice and reagents. A.S., A.C.N., P.G., D.H. and J.A.G. were involved in the study design and manuscript writing. J.A.G. coordinated the study. All authors analysed data they generated, discussed results and commented on the manuscript. A.S., E.V. and Mi.M. contributed equally to this work.

Author information



Corresponding author

Correspondence to Jean-Antoine Girault.

Supplementary information

Supplementary Information

The file contains Supplementary Figures 1-13 with Legends and Supplementary Table 1 with ANOVA analysis of results presented in Figures 1-4 (PDF 5984 kb)

Supplementary Movie

The file contains Supplementary Movie 1 with time lapse video of the nuclear translocation of DARPP-32-GFP in transfected a striatal neuron treated with leptomycin B (10 ng/ml). (AVI 6360 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Stipanovich, A., Valjent, E., Matamales, M. et al. A phosphatase cascade by which rewarding stimuli control nucleosomal response. Nature 453, 879–884 (2008).

Download citation

Further reading


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing